Phenol derivatives have a wide variety of clinical uses. Some are used as bacteriostatic stabilizers in parenteral drug formulations. We have recently shown that 4-chloro-3-methylphenol (4-chloro-m-cresol) and benzylalcohol both block muscle sodium channels in a voltage-dependent manner (Haeseler et al., Br. J. Pharmacol., 128 (1999) 1259-67; Haeseler et al., Br. J. Pharmacol., 130 (2000) 1321-1330). For the anesthetic propofol (2,6-di-isopropylphenol), various voltage-operated (Rehberg & Duch, Anaesthiology, 91 (1999) 512-20; Saint, Br. J. Pharmacol., 124 (1998) 655-662) and ligand-gated (Sanna et al., Br. J. Pharmacol., 126 (1999) 1444-54) channels, mainly in the central nervous system, have been identified as possible targets. Integrated into larger molecules, phenol derivatives with single substituents form the aromatic tail of most local anesthetics and class Ib antidysrhythmic drugs. The effect of the local anesthetic lidocaine (2-diethylamino-2′,6′-dimethylacetanilide) on voltage-operated sodium channels in different excitable tissues has been extensively studied. Lidocaine-induced sodium channel blockade is characterized by a higher affinity of the drug for fast and slow inactivated channels compared with the resting state, and by prolonged recovery from inactivation, introducing a second, slow component representing drug dissociation from inactivated channels (Balser et al., J. Gen. Physiol., 107 (1996) 643-658; Bean et al., J. Gen. Physiol., 81 (1983) 613-642; Fan et al., J. Physiol., 81 (1996) 275-286; Scheuer, J. Gen. Physiol., 113 (1999) 3-6; Vedantham & Cannon, J. Gen. Physiol., 113 (1999) 7-16). Several studies have addressed the structural requirements for pharmacological effects (Ehring et al., J. Pharmacol. Exp. Therapeut., 244 (1988) 479-92; Sheldon et al., Mol. Pharmacol., 39 (1991) 609-614), but have not provided clues about which parts of the lidocaine molecule are responsible for its state-dependent interaction with the sodium channel. The approach of dissecting the lidocaine molecule into phenol and diethylamide (Zamponi & French, Biophys. J. 65 (1993) 2335-2347) did not take into account the fact that the aromatic group of the parent compound is a methylated phenol derivative. Although phenol block mimicked slow block of cardiac sodium channels seen with lidocaine, blocking potency was an order of magnitude lower and skeletal muscle sodium channels were only minimally affected.